Biochemistry and Pharmacology - Research Publications

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Author: Cheng, Heung × Author: HOSSAIN, IQBAL KAZI MOHAMMAD × Author: JARASRASSAMEE, BOONYARIN ×

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    Structural elements and allosteric mechanisms governing regulation and catalysis of CSK-family kinases and their inhibition of Src-family kinases
    Ia, KK ; Mills, RD ; Hossain, MI ; Chan, K-C ; Jarasrassamee, B ; Jorissen, RN ; Cheng, H-C (TAYLOR & FRANCIS LTD, 2010-10)
    C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are endogenous inhibitors constraining the activity of the oncogenic Src-family kinases (SFKs) in cells. Both kinases suppress SFKs by selectively phosphorylating their consensus C-terminal regulatory tyrosine. In addition to phosphorylation, CHK can suppress SFKs by a unique non-catalytic inhibitory mechanism that involves tight binding of CHK to SFKs to form stable complexes. In this review, we discuss how allosteric regulators, phosphorylation, and inter-domain interactions interplay to govern the activity of CSK and CHK and their ability to inhibit SFKs. In particular, based upon the published results of structural and biochemical analysis of CSK and CHK, we attempt to chart the allosteric networks in CSK and CHK that govern their catalysis and ability to inhibit SFKs. We also discuss how the published three-dimensional structure of CSK complexed with an SFK member sheds light on the structural basis of substrate recognition by protein kinases.
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    A facile, click chemistry-based approach to assembling fluorescent chemosensors for protein tyrosine kinases
    Kamaruddin, MA ; Ung, P ; Hossain, MI ; Jarasrassamee, B ; O'Malley, W ; Thompson, P ; Scanlon, D ; Cheng, H-C ; Graham, B (PERGAMON-ELSEVIER SCIENCE LTD, 2011-01)
    A group of fluorophore-labeled peptide substrates of Src kinases have been synthesized with the aid of click chemistry. Some of the generated peptides exhibit an increase in fluorescence upon phosphorylation and are capable of detecting Src kinases with high sensitivity and specificity. Their availability permits real-time activity measurement of aberrantly activated oncogenic Src kinases in the crude lysate of chronic myelogenous leukemia cells. These new chemosensor peptides are highly useful tools that can be used for high-throughput screening to search for small molecule inhibitors of Src kinases as potential therapeutics for cancer treatment.